The long-term aim of this project is to reduce or eliminate the serious adverse events associated with cellular immunotherapy used to treat cancer. The current impressive efficacy of chimeric antigen receptor (CAR) T cell therapies is often accompanied by a well-known toxicity stemming from the large release of cytokines from activated immune cells, known as a 'cytokine storm'. An ideal cancer therapy would be effective, selective, permanent, and safe. The immune system has the ability to specifically recognize and attack tumor cells and their supportive microenvironments, while sparing nearby normal cells. We have developed a novel therapy that has met these marks through the use of a patient's own immune cells. In this therapy, a patient's T-cells will be modified to express a NKG2D based CAR, expanded, and then returned to the patient. Although the promise of this CAR therapy is impressive, the potential use may be hampered by cytokine storm SAEs as observed for other CAR therapies in the clinic. The work proposed here is a major step toward reduction of cytokine storm-mediate toxicity of T-cell-based therapies. The product to be developed is a combination NKG2D CAR T cell therapy with anti-GM-CSF antibodies. In murine models, genetic ablation of GM-CSF has preempted cytokine storm entirely while retaining efficacy demonstrating that GM-CSF is a key component of the cytokine storm responsible for the observed acute toxicity. This combination therapy has the potential to significantly increase the therapeutic window, increase safety for patients, and allow clinicians to treat more aggressively and with more confidence. GM-CSF upregulation was observed in human patients treated with CAR therapies, underscoring the clinical relevance and potential for this approach. In this Phase I SBIR proposal, we will determine the extent to which neutralizing antibodies against GM-CSF increase the therapeutic window of NKG2D CAR T cells. We will determine the extent to which the GM-CSF antibodies allow the infusion of high cell doses of NKG2D CAR T cells without toxicity. Furthermore, we will investigate the optimal time of administration of the antibodies to prevent acute toxicity, and we will measure whether the antibodies affect the efficacy of NKG2D CAR T cells. These studies will advance CAR-targeted therapies in general and, if successful, yield a promising therapeutic platform with broad applicability that is ready fr clinical development. At the end of this Phase I project, we will have achieved key goals on the critical path to move this potentially broadly applicable intervention toward the clinic.